WO2008045189A2 - Formulations pharmaceutiques à base aqueuse de promédicaments hydrosolubles du propofol - Google Patents

Formulations pharmaceutiques à base aqueuse de promédicaments hydrosolubles du propofol Download PDF

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Publication number
WO2008045189A2
WO2008045189A2 PCT/US2007/020351 US2007020351W WO2008045189A2 WO 2008045189 A2 WO2008045189 A2 WO 2008045189A2 US 2007020351 W US2007020351 W US 2007020351W WO 2008045189 A2 WO2008045189 A2 WO 2008045189A2
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WO
WIPO (PCT)
Prior art keywords
formulation
propofol
formulations
prodrug
water
Prior art date
Application number
PCT/US2007/020351
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English (en)
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WO2008045189A3 (fr
Inventor
Kanaiyalal R. Patel
Stephen Dordunoo
David Keller
Original Assignee
Eisai Corporation Of North America
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai Corporation Of North America filed Critical Eisai Corporation Of North America
Priority to CN2007800367199A priority Critical patent/CN101583271B/zh
Priority to AU2007307301A priority patent/AU2007307301A1/en
Priority to CA002662643A priority patent/CA2662643A1/fr
Priority to EP07838542A priority patent/EP2068630A4/fr
Priority to US12/443,583 priority patent/US20100311698A1/en
Priority to JP2009531387A priority patent/JP2010505826A/ja
Publication of WO2008045189A2 publication Critical patent/WO2008045189A2/fr
Publication of WO2008045189A3 publication Critical patent/WO2008045189A3/fr
Priority to IL197913A priority patent/IL197913A0/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • propofol has a range of other biological and medical applications. For example, it has been reported to be an antiemetic [McCollum JSC et al., Anesthesia 43 (1988) 239], an anti-epileptic [Chilvers CR, Why PS, Anesthesia 45 (1990) 995], and an anti-pruritic [Borgeat et al., Anesthesiology 76 (1992) 510]. Anti-emetic and anti-pruritic effects are typically observed at subhypnotic doses, i.e., at doses that achieve propofol plasma concentrations lower than those required for sedation or anesthesia.
  • Antiepileptic activity is observed over a wider range of plasma concentrations [Borgeat et al., Anesthesiology 80 (1994) 642].
  • Short-term intravenous administration of subanesthetic doses of propofol has also been reported to be remarkably effective in the treatment of intractable migraine and nonmigrainous headache [Krusz JC, et al., Headache, 40 (2000) 224-230]. It has further been speculated that propofol may be useful as an anxiolytic [Kurt et al., Pol. J. Pharmacol.
  • neuroprotectant [Velly et al., Anesthesiology 99 (2003) 368-75]
  • muscle relaxant [O'Shea et al., J. Neurosci. 24 (2004) 2322-7] and, due to its antioxidant properties in biological systems, may further be useful in the treatment of inflammatory conditions, especially inflammatory conditions with a respiratory component, and in the treatment of neuronal damage related to neurodegeneration or trauma.
  • Such conditions are believed to be associated with the generation of reactive oxygen species and therefore amenable to treatment with antioxidants. See, e.g., U.S. Patent 6,254,853 to Hendler et al.
  • Propofol typically is formulated for clinical use as a oil-in-water emulsion.
  • the formulation has a limited shelf-life and has been shown to be sensitive to bacterial or fungal contamination, which has led to instances of postsurgical infections [Bennett SN et al., N Engl J Med 333 (1995) 147]. Due to the dense, white color of the formulation, bacterial or fungal contamination cannot be detected by visual inspection of the vial in the first instance.
  • Induction doses of propofol are also known to have a marked hypotensive effect, which is dose- and plasma concentration-dependent [Reves et al., supra ⁇ .
  • the hypotension associated with peak plasma levels after rapid bolus injection of propofol sometimes requires the use of controlled infusion pumps or the breaking-up of the induction bolus dose into several smaller incremental doses.
  • the short duration of unconsciousness caused by bolus induction doses renders propofol suitable for only brief medical procedures.
  • propofol for induction and/or maintenance of anesthesia must normally be administered in an in-patient setting under the supervision of an anesthesiologist, and is often considered inappropriate for use by non-anesthesiologists in an ambulatory or day case setting.
  • propofol Compared with the widely used sedative midazolam or other such agents, propofol provided similar or better sedative effects when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation were measured [see Fulton B and Sorkin EM, Drugs 50 (1995) 636].
  • the faster recovery and similar or less amnesia associated with propofol makes it an attractive alternative to other sedatives, particularly for patients requiring only short sedation.
  • the usefulness of propofol for patients requiring longer sedation is less well established.
  • propofol in its commercially available formulations is generally recognized as not suitable for other than parenteral administration, and generally must be injected or infused intravenously. While propofol is administered intravenously in a clinical setting, it has been suggested that it could be delivered for certain indications via other non-oral routes, such as via inhalation using a nebulizer, transmucosally through the epithelia of the upper alimentary tract, or rectally in the form of a suppository [see, e.g. Cozanitis, D.A., et ah, Acta Anaesthesiol. Scand. 35 (1991) 575-7; see also U.S. Patents 5,496,537 and 5,288,597]. However, the poor bioavailability of propofol when administered by any other than the intravenous route has hampered the development of such treatments.
  • prodrugs differ from propofol in that the 1 -hydroxy-group of propofol is replaced with a phosphonooxymethyl ether group:
  • the prodrug is believed to undergo hydrolysis by endothelial cell surface alkaline phosphatases to release propofol.
  • antioxidants can be consumed when formulations, are packaged in containers that are more permeable to oxygen, especially many types of plastic containers such as blow-filled seal (BFS) vials. It would be desirable to develop an aqueous formulation that exhibits stability over extended periods of time, while avoiding the need for packaging in substantially oxygen- impermeable containers.
  • BFS blow-filled seal
  • the present invention is directed to aqueous-based pharmaceutical formulations of water-soluble prodrugs of propofol.
  • the pharmaceutical formulation comprises in an aqueous medium a therapeutically effective amount of a compound represented by Formula I:
  • each Z is independently selected from the group consisting of hydrogen, alkali metal ion, and amine.
  • the aqueous formulation is substantially free of antioxidant.
  • the formulation includes a plurality, preferably two, buffers.
  • the buffers can be selected to maintain pH within a prescribed range so that the formulation is stable for extended periods of time by minimizing degradation of the prodrug.
  • a combination of 2-amino-2-hydroxymethyl-l,3- propanediol (TRIS) and sodium bicarbonate is used as a buffer system.
  • the formulation is buffered in a pH range of about 8 to about 12, preferably from about 9 to about 10. It has been found that degradation of the prodrug is pH dependent. When pH is maintained within this range, the formulations exhibit stability over extended periods of time, without the need for an antioxidant.
  • the aqueous formulations of the present invention are particularly useful as intravenous injections.
  • the formulations are stable for extended periods of time, and are suitable for packaging in plastic containers such as blow-filled seal (BFS) vials.
  • BFS blow-filled seal
  • compositions of the present invention comprise in aqueous medium a therapeutically effective amount of a water-soluble prodrug represented by Formula I:
  • each Z is independently selected from the group consisting of hydrogen, alkali metal ion, and amine.
  • the formulation is substantially free of antioxidant.
  • the aqueous-based formulations may also contain other components, such as a tonicity modifier and/or buffer(s).
  • the relative amount of the prodrug in the formulation can vary over a wide range depending on a variety of factors including but not limited to the identity of the prodrug, the bioactivity of the parent drug for a particular disorder being treated, and the intended mode of administration.
  • the relative amount of the prodrug in the formulation most often ranges from about 0.5 to about 20% (w/v), more usually from about 1 to about 10%.
  • Any pharmaceutically acceptable aqueous medium such as water of sufficiently high purity, may be used in the formulations.
  • the pH of the formulation preferably is maintained to provide long-term stability of the formulation at room temperature.
  • the formulation is buffered in a pH range of about 8 to about 12, often from about 9 to about 10 or from about 8.6 to about 9.5. These pH ranges minimize hydrolysis of the prodrug while, at the same time, are suitable for intravenous administration.
  • the solution may be buffered using any buffer effective over this pH range, e.g., carbonate, phosphate, borate, or glycine.
  • the amount of buffer most often ranges from about 2 to about 50 mrnol, more usually from about 5 to about 25 mmol.
  • a combination of tromethamine (2-amino-2-hydroxymethyl- 1,3-propanediol), commonly referred to as TRIS 5 and sodium bicarbonate is used as a buffer system. It was found that when 2-amino-2-hydroxymethyl-l,3-propanediol is used alone as a buffer, the pH of the formulation tends to decrease over time. When sodium bicarbonate is used alone as a buffer, the pH tends to increase over time. When 2-amino- 2-hydroxymethyl-l,3-propanediol and sodium bicarbonate are used together, pH remains more stable over time.
  • tonicity i.e., osmolality
  • osmolality is essentially the same as normal physiological fluids in order to prevent post-administration swelling or rapid absorption of the composition because of differential ion concentrations between the composition and physiological fluids.
  • a tonicity modifier can be added.
  • the amount of tonicity modifier used most often ranges from about 0.1 to about 1% (w/v).
  • suitable tonicity modifiers include sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride.
  • a preservative may be included, such as benzyl alcohol.
  • the formulation also may contain co-solvents such as polyethylene glycol (PEG 200, PEG 400), propylene glycol, and/or ethanol. Concentrations of the co-solvents can vary over a wide range, most often from 0 to about 20%.
  • the formulations can be prepared without an antioxidant as described herein, antioxidants can be used, for example when the formulation is packaged with materials having lower oxygen permeability so as to avoid antioxidant loss.
  • Non-limiting examples of antioxidants include monothioglycerol (MTG), glutathione, citric acid, ascorbic acid, sodium metabisulfite, and sodium sulfite.
  • EDTA a metal chelator, provides protection from catalytic oxidation of phenols.
  • the formulations may be administered via any suitable route of administration.
  • Formulations for intravenous injection may be packaged, for example, in a glass vial, in a pre-f ⁇ lled syringe, or in an ampoule. Because the formulations do not require an antioxidant, the formulations need not be packaged in oxygen-impermeable containers such as glass vials, but alternatively can be packaged in a variety of types of plastic containers such as blow-filled seal (BFS) vials.
  • BFS blow-filled seal
  • the formulations may be administered with standard IV diluent solutions, e.g., D5W, normal saline, or Lactated Ringer's solution.
  • the formulations can be packaged in blow- filled seal vials by vacuum sealing in pouches made from an oxygen- and carbon dioxide barrier material, such as aluminum foil, and/or by adding oxygen- and carbon dioxide scavengers to a packaging material.
  • blow-filled seal containers can be constructed using materials (e.g., multilayer) which have lower permeability to oxygen and carbon dioxide. As illustrated in Table I below, each of these techniques is effective for stabilizing pH and avoiding loss of antioxidant.
  • Suitable dosages can be ascertained depending on such factors as the identity of the prodrug and the type of the disorder being treated. Dosages may be, for example, in the range of about 0.1 to about 100 mg/kg of body weight, or about 5 to 500 mg/ml. As will be apparent to persons skilled in the art, many factors that modify the action of the drug will be taken into account in determining the dosage including the age, sex, diet and physical conditions of the patient.
  • an anesthesiologist skilled in the art of anesthesia will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a formulation of the present invention.
  • the dosage, mode and schedule of administration are not particularly restricted, and will vary with the particular indication.
  • the formulation may be administered parenterally.
  • the dosage may be, for example, in the range of 0.5 to 10 mg/kg administered according to procedures for induction of general anesthesia or maintenance of general anesthesia.
  • the formulation may be administered by parenteral infusion
  • the dosage may be, for example, in the range of 2 ⁇ g/kg/min to 800 ⁇ g/kg/min administered according to procedures for maintenance of general anesthesia, initiation and maintenance of MAC sedation or initiation and maintenance of ICU sedation.
  • NMT LOQ not more than limit of quantitation
  • This example illustrates the stability of an O-phosphonooxymethyl propofol (40 mg/mL) formulation prepared without antioxidant.
  • the formulation contained 0.12% (w/v) 2-amino-2-hydroxymethyl-l,3-propanediol and 10 mmol sodium bicarbonate (pH 9.0 - 9.3).
  • Table IV As illustrated in Table IV below, under accelerated stability conditions (40 0 C, 75% RH) the formulation remained colorless after 3 months storage and pH remained substantially constant.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Anesthesiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques à base aqueuse de promédicaments hydrosolubles du propofol. Les formulations comprennent, dans un milieu aqueux, une quantité efficace du promédicament hydrosoluble du propofol en absence d'oxidant. Les formulations sont particulièrement utiles en tant qu'injections intraveineuses. Les formulations sont de préférence tamponnées à un pH approprié pour minimiser la dégradation du promédicament pendant le stockage. Les formulations peuvent être préparées sans utiliser de co-solvants ou de tensioactifs nocifs et sont stables à température ambiante pendant des durées prolongées.
PCT/US2007/020351 2006-10-05 2007-09-20 Formulations pharmaceutiques à base aqueuse de promédicaments hydrosolubles du propofol WO2008045189A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN2007800367199A CN101583271B (zh) 2006-10-05 2007-09-20 丙泊酚水溶性前药的水基药物制剂
AU2007307301A AU2007307301A1 (en) 2006-10-05 2007-09-20 Aqueous based pharmaceutical formulations of water-soluble prodrugs of propofol
CA002662643A CA2662643A1 (fr) 2006-10-05 2007-09-20 Formulations pharmaceutiques a base aqueuse de promedicaments hydrosolubles du propofol
EP07838542A EP2068630A4 (fr) 2006-10-05 2007-09-20 Formulations pharmaceutiques à base aqueuse de promédicaments hydrosolubles du propofol
US12/443,583 US20100311698A1 (en) 2006-10-05 2007-09-20 Aqueous based pharmaceutical formulations of water-soluable prodrugs of propofol
JP2009531387A JP2010505826A (ja) 2006-10-05 2007-09-20 プロポフォールの水溶性プロドラッグの水ベースの薬学的製剤
IL197913A IL197913A0 (en) 2006-10-05 2009-04-05 Aqueous based pharmaceutical formulations of water-soluble prodrugs of propofol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82830706P 2006-10-05 2006-10-05
US60/828,307 2006-10-05

Publications (2)

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WO2008045189A2 true WO2008045189A2 (fr) 2008-04-17
WO2008045189A3 WO2008045189A3 (fr) 2008-07-31

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US (1) US20100311698A1 (fr)
EP (1) EP2068630A4 (fr)
JP (1) JP2010505826A (fr)
KR (1) KR20090059136A (fr)
CN (1) CN101583271B (fr)
AU (1) AU2007307301A1 (fr)
CA (1) CA2662643A1 (fr)
IL (1) IL197913A0 (fr)
WO (1) WO2008045189A2 (fr)

Cited By (1)

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WO2009104054A2 (fr) * 2007-10-15 2009-08-27 University Of Kansas Compositions pharmaceutiques contenant des dérivés hydrosolubles de propofol et leurs méthodes d'administration par voie respiratoire

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CN101716149B (zh) * 2009-11-30 2013-04-10 宜昌人福药业有限责任公司 一种新的前体药物制剂
CN105310977A (zh) * 2014-06-27 2016-02-10 江苏华泰晨光药业有限公司 一种葡萄糖基化丙泊酚水溶液型注射剂及其制备方法
US11331271B2 (en) 2016-05-27 2022-05-17 The Johns Hopkins University Buccal, sublingual and intranasal delivery of fospropofol
US11628178B2 (en) 2019-03-26 2023-04-18 Epalex Corporation Fospropofol methods and compositions
US11547714B2 (en) 2020-02-05 2023-01-10 Epalex Corporation Fospropofol salts, methods and compositions
US11439653B1 (en) 2021-03-30 2022-09-13 Epalex Corporation Fospropofol formulations
US11478490B1 (en) 2021-03-30 2022-10-25 Epalex Corporation Fospropofol formulations

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US6204257B1 (en) * 1998-08-07 2001-03-20 Universtiy Of Kansas Water soluble prodrugs of hindered alcohols
US20040022740A1 (en) * 2001-07-10 2004-02-05 Baker William R. Macrolide formulations for inhalation and methods of treatment of endobronchial infections
UA76802C2 (uk) * 2001-12-28 2006-09-15 Мгі Гп, Інк. Фармацевтичний препарат водорозчинних проліків пропофолу на водній основі (варіанти)
WO2003086413A1 (fr) * 2002-04-08 2003-10-23 Guilford Pharmaceuticals, Inc. Compositions pharmaceutiques contenant des promedicaments hydrosolubles a base de propofol et procedes d'administration associes
EP1520573A1 (fr) * 2003-09-30 2005-04-06 Total Petrochemicals Research Feluy Sachets pressables en polyéthylène
CA2548216A1 (fr) * 2003-12-17 2005-06-30 Mgi Gp, Inc. Procedes pour administrer des promedicaments de propofol solubles dans l'eau pour une sedation amelioree
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CN101355953B (zh) * 2005-11-08 2014-07-09 味之素株式会社 麻醉苏醒促进剂

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009104054A2 (fr) * 2007-10-15 2009-08-27 University Of Kansas Compositions pharmaceutiques contenant des dérivés hydrosolubles de propofol et leurs méthodes d'administration par voie respiratoire
WO2009104054A3 (fr) * 2007-10-15 2009-11-19 University Of Kansas Compositions pharmaceutiques contenant des dérivés hydrosolubles de propofol et leurs méthodes d'administration par voie respiratoire

Also Published As

Publication number Publication date
EP2068630A4 (fr) 2010-12-29
CN101583271A (zh) 2009-11-18
WO2008045189A3 (fr) 2008-07-31
JP2010505826A (ja) 2010-02-25
AU2007307301A1 (en) 2008-04-17
IL197913A0 (en) 2009-12-24
EP2068630A2 (fr) 2009-06-17
US20100311698A1 (en) 2010-12-09
CN101583271B (zh) 2013-07-17
CA2662643A1 (fr) 2008-04-17
KR20090059136A (ko) 2009-06-10

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